Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation

Abstract

Importance: The comparative effectiveness of rivaroxaban and apixaban, the most frequently prescribed oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation, is uncertain.

Objective: To compare major ischemic and hemorrhagic outcomes in patients with atrial fibrillation treated with rivaroxaban or apixaban.

Design, setting, and participants: Retrospective cohort study using computerized enrollment and claims files for US Medicare beneficiaries 65 years or older. Between January 1, 2013, and November 30, 2018, a total of 581 451 patients with atrial fibrillation began rivaroxaban or apixaban treatment and were followed up for 4 years, through November 30, 2018.

Exposures: Rivaroxaban (n = 227 572) and apixaban (n = 353 879), either standard or reduced dose.

Main outcomes and measures: The primary outcome was a composite of major ischemic (stroke/systemic embolism) and hemorrhagic (intracerebral hemorrhage/other intracranial bleeding/fatal extracranial bleeding) events. Secondary outcomes were nonfatal extracranial bleeding and total mortality (fatal ischemic/hemorrhagic event or other death during follow-up). Rates, hazard ratios (HRs), and rate differences (RDs) were adjusted for baseline differences in comorbidity with inverse probability of treatment weighting.

Results: Study patients (mean age, 77.0 years; 291 966 [50.2%] women; 134 393 [23.1%] receiving reduced dose) had 474 605 person-years of follow-up (median [IQR] of 174 [62-397] days). The adjusted primary outcome rate for rivaroxaban was 16.1 per 1000 person-years vs 13.4 per 1000 person-years for apixaban (RD, 2.7 [95% CI, 1.9-3.5]; HR, 1.18 [95% CI, 1.12-1.24]). The rivaroxaban group had increased risk for both major ischemic events (8.6 vs 7.6 per 1000 person-years; RD, 1.1 [95% CI, 0.5-1.7]; HR, 1.12 [95% CI, 1.04-1.20]) and hemorrhagic events (7.5 vs 5.9 per 1000 person-years; RD, 1.6 [95% CI, 1.1-2.1]; HR, 1.26 [95% CI, 1.16-1.36]), including fatal extracranial bleeding (1.4 vs 1.0 per 1000 person-years; RD, 0.4 [95% CI, 0.2-0.7]; HR, 1.41 [95% CI, 1.18-1.70]). Patients receiving rivaroxaban had increased risk of nonfatal extracranial bleeding (39.7 vs 18.5 per 1000 person-years; RD, 21.1 [95% CI, 20.0-22.3]; HR, 2.07 [95% CI, 1.99-2.15]), fatal ischemic/hemorrhagic events (4.5 vs 3.3 per 1000 person-years; RD, 1.2 [95% CI, 0.8-1.6]; HR, 1.34 [95% CI, 1.21-1.48]), and total mortality (44.2 vs 41.0 per 1000 person-years; RD, 3.1 [95% CI, 1.8-4.5]; HR, 1.06 [95% CI, 1.02-1.09]). The risk of the primary outcome was increased for rivaroxaban in both those receiving the reduced dose (27.4 vs 21.0 per 1000 person-years; RD, 6.4 [95% CI, 4.1-8.7]; HR, 1.28 [95% CI, 1.16-1.40]) and the standard dose (13.2 vs 11.4 per 1000 person-years; RD, 1.8 [95% CI, 1.0-2.6]; HR, 1.13 [95% CI, 1.06-1.21]) groups.

Conclusions and relevance: Among Medicare beneficiaries 65 years or older with atrial fibrillation, treatment with rivaroxaban compared with apixaban was associated with a significantly increased risk of major ischemic or hemorrhagic events.

Figure 1.. Selection and Inclusion of Participants in a Study of the Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Atrial Fibrillation

^aApixaban (2.5 mg or 5 mg twice/d) or rivaroxaban (15 mg or 20 mg once/d). ^bDeep vein thrombosis/pulmonary embolism, hip/knee replacement, femur/tibia/patella fracture, thrombectomy, or chronic hypercoagulable state. ^cStage 4 or 5 or end-stage chronic kidney disease. ^dDiagnosis of hyperthyroidism or open coronary artery bypass graft/open cardiac valve surgery.

Figure 2.. Primary Outcome in a Study of the Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Atrial Fibrillation

Adjusted cumulative incidence of major ischemic (ischemic stroke or systemic embolism) or hemorrhagic (hemorrhagic stroke, other intracranial bleeding, fatal extracranial bleeding) events. The median (IQR) follow-up time was 5.8 (2.1-13.2) months. Adjusted with inverse probability of treatment weighting; the variables used in the adjustment are shown in eTable 5 in the Supplement.

Figure 3.. Outcomes by Medication Dose in a Study of the Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Atrial Fibrillation

Adjusted incidence of study outcomes according to anticoagulant dose. Rates, rate differences, and hazard ratios were adjusted with inverse probability of treatment weighting; the variables used in the adjustment are shown in eTable 5 in the Supplement. See eTable 9 in the Supplement for numbers of events.